This invention relates to novel compositions with affinity for a monoamine transporter, such as the dopamine, norepinephrine, or serotonin transporter, in brain and in peripheral tissues.
Monoamine transporters play a variety of roles, and compounds with affinity for the monoamine transporters have been proposed for therapy and/or diagnosis of medical indications that include (but are not limited to) attention deficit hyperactivity disorder (ADHD), Parkinson""s disease, cocaine addiction, smoking cessation, weight reduction, obsessive-compulsive disorder, various forms of depression, traumatic brain injury, stroke, and narcolepsy.
The dopamine transporter (DAT) in particular is a primary mechanism for terminating the effects of synaptic dopamine and maintaining homeostatic levels of extracellular dopamine in brain. Giros et al., Nature 379: 696-612 (1996). The dopamine transporter is a principal target of therapeutic and psychostimulant drugs of abuse. For example, the dopamine transporter is an important target of drugs (including methylphenidate, pemoline, amphetamine and bupropion) used to treat ADHD. Seeman and Madras, Mol. Psychiatry 3:386-396 (1998); Cyr and Brown, Drugs, 56:215-223 (1998); Biederman, J. Clin. Psychiatry 59: 4-16 (1998); Riggs et al., J. Am Acad. Child Adolesc. Psychiatry 37:1271-1278 (1999). The dopamine transporter is also a principal target of brain imaging agents used, for example, diagnostically.
It has been suggested that the therapeutic benefit of benztropin (Cogenting) for Parkinson""s disease results in part from blocking dopamine transport thereby increasing synaptic dopamine. Coyle and Snyder, J. Pharmacol. Exp. Ther.,170:221-319 (1969).
The antidepressant bupropion apparently is also a monoamine transport inhibitor [Hirschfeld, J. Clin. Psychiatry 17:32-35 (1999)], and it has been suggested as a treatment to aid smoking cessation. Jorenby et al., N. Engl. J Med., 340:685-691 (1999); McAfee et al., N. Engl. J. Med., 338:619 (1998).
The dopamine transporter has been identified as an effective marker for dopamine terminals in Parkinson""s disease. Kaufman and Madras, Synapse 9: 43-49 (1991). Brain imaging of the transporter in humans with Parkinson""s disease and in animals with experimentally produced Parkinsonism has confirmed the usefulness of the dopamine transporter in this application. Fischman et al., Synapse 29: 128-141, 1998, Seibyl et al., Ann. Neurol. 38:589-598.
The serotonin transporter (SERT) regulates extracellular serotonin levels. It is a principal target of effective drugs (known as serotonin-selective reuptake inhibitors or SSRI""s) used to treat melancholic depression, atypical depression, dysthymia and obsessive-compulsive disorder. It also is a conduit of entry into serotonin containing neurons of neurotoxic substituted amphetamines. Selective imaging agents that label the serotonin transporter would be useful to investigate the status of the transporter in depression [Malison et al. Bio. Psychiatry 44:1090-1098 (1998)], alcoholism [Heinz et al. Am. J. Psychiatry 155:1544-1549 (1998)], obsessive-compulsive disorder, and substituted amphetamine abusers [McCann et al., Lancet 352:1433-1437 (1998); Semple et al., Br., J. Psychiatry 175: 63-39 (1999)]. There are various reports generally dealing with individual serotonin transporter imaging agents. Acton et al. Eur. J. Nucl. Med. 26:1359-1362 (1999); Szabo et al. J. Cereb. Blood Flow Metab. 19:967-981 (1999); Oya et al. J. Med Chem. 42:333-335 (1999).
Norepinephrine regulates mood, is involved in learning and memory, and controls endocrine and autonomic functions. Dysfunction of norepinephrine neurotransmission has been implicated in depression, cardiovascular and thermal pathophysiology. The norepinephrine transporter (NET) regulates extracellular levels of norepinephrine in brain, in heart, and in the sympathetic nervous system. Clinically, the norepinephrine transporter is a principal target of selective or non-selective anti-depressant drugs and stimulant drugs of abuse such as cocaine and amphetamines. Blockade of the norepinephine transporter is implicated in appetite suppression. Gehlert et al. J. Pharmacol. Exp. Ther. 287:122-127 (1998). Imaging of the norepinephrine transporter may also be useful for viewing the status of sympathetic innervation in the heart and in other adrenergic terminals, and for detecting neuroblastomas. Hadrich et al. J. Med. Chem. 42:3010-3018 (1999); Raffel et al., J. Nucl. Med. 40:323-330 (1999).
It is desirable to avoid unwanted side effects of treatments targeting monoamine transporters, to the extent possible: It is also desirable to produce efficient and effective diagnostics for various conditions involving monoamine transporters.
The invention features compounds of two general classes that have high and selective monoamine transport affinity. Featured compounds of the first class (which we term oxaindanes) generally have the following formula: 
WHERE:
* indicates a chiral center, and each chiral center, independently, may be R, S, or R/S.
xe2x80x94X=xe2x80x94CH2R1; xe2x80x94CHR1R5; xe2x80x94CR1xe2x95x90O; xe2x80x94CR6xe2x95x90O; xe2x80x94Oxe2x80x94R1; xe2x80x94SR1; xe2x80x94SOR6; xe2x80x94SO2R6; xe2x80x94SO2NHR1; or xe2x80x94CHxe2x95x90CR1R5 and where:
a. xe2x80x94R1 and xe2x80x94R5 are independently selected from: xe2x80x94H; xe2x80x94CH3; xe2x80x94CH2CH3; or xe2x80x94CH2(CH2)mCH3, where m=0, 1, 2, or 3; PROVIDED THAT,
when X=xe2x80x94Oxe2x80x94R1, then R1xe2x89xa0H; and
b. xe2x80x94R6 is ""selected from: xe2x80x94OH; xe2x80x94OCH3; xe2x80x94NHR1; xe2x80x94O-alkyl; xe2x80x94O-alkenyl; xe2x80x94O-alkynyl; xe2x80x94O-allyl; xe2x80x94O-iodoallyl; -alkyl; -alkenyl; -alkynyl; -allyl; -isopropyl; and -isobutyl.
xe2x80x94Ar=either
a) phenyl substituted at any two positions with R3a and R3b, where R3a and R3b are as defined in options xe2x80x9cI.xe2x80x9d or xe2x80x9cII.xe2x80x9d, below; or
b) 1-napththyl or 2-naphthyl, substituted at any two positions with R3a, and R3b where R3a and R3b are as defined in option xe2x80x9cI.xe2x80x9d, below);
OPTION I for R3a, and R3b (phenyl or naphthyl substitutions)
xe2x80x94R3a and xe2x80x94R3b are independently selected from: xe2x80x94H; xe2x80x94Br; xe2x80x94Cl; xe2x80x94I; xe2x80x94F; xe2x80x94H; xe2x80x94OCH3; xe2x80x94CF3; xe2x80x94NO2; xe2x80x94NH2; xe2x80x94CN; xe2x80x94NHCOCH3, xe2x80x94C(CH3)3, xe2x80x94(CH2)qCH3 where q=0-6; xe2x80x94COCH3; xe2x80x94F (at the 2, 3 or 4 position), xe2x80x94Cl (at the 2, 3 or 4 position); xe2x80x94I (at the 2, 3 or 4 position); alkyl; alkenyl; alkynyl; allyl; iospropyl; isobutyl; alkyl; -alkylN2S2chelator; -alkylN2S2Tc chelator, such that N2S2 is part of a chelating moiety such as those known in the art which contain two nitrogens and two sulfur atoms, in addition to carbon and optionally other heteroatoms, see, for example, O""Neil et al., Bioconjugate Chem. 5:182-193 (1994); O""Neil et al., Inorg. Chem. 33:319-323 (1994); Kung et al., J. Nucl. Med. 27:1051 (1986); Kung et al., J. Med. Chem. 28: 1280-1284 (1985), hereby incorporated by reference; or COR7, where R7 is defined below;
xe2x80x83OR
OPTION II. for R3a, and R3b (phenyl substitutions)
xe2x80x94R3a and xe2x80x94R3b as a pair are independently selected from the following pairs: 3,4-diCl; 3,4, diOH; 3,4-diOAc; 3,4-diOCH3; 3-OH,4-Cl; 3-OH,4-F; 3-Cl,4-OH; or 3-F,4-OH;
n=0 or 1;
xe2x80x94R2=xe2x80x94COOCH3; xe2x80x94COR 7; -alkyl; -alkenyl; -allyl; -iodoallyl; -alkynyl; -isoxazole; -oxadiazole; -oxazole; -alkylN2S2 chelator, xe2x80x94O-alkylN2S2 chelator. -alkylN2S2Tc chelator; xe2x80x94O-alkylN2S2Tc chelator; where,
xe2x80x94R7 is xe2x80x94HR8; morpholinyl; piperidinyl; xe2x80x94CH3; xe2x80x94CH2CH3; xe2x80x94CH2(CH2)rCH3 where r=0, 1, 2, or 3; alkyl; alkenyl; alkynyl; allyl; isopropyl; iodoallyl; O-iodoallyl; -isobutyl; xe2x80x94CH2SO2; -alkylN2S2 chelator; -alkylN2S2Tc chelator; O-alkylN2S2 chelator, or xe2x80x94O-alkylN2S2Tc chelator; and xe2x80x94R8 is -alkyl; -alkenyl; -allyl; iodoallyl; -alkynyl; -isoxazole; -oxadiazole; -oxazole; -alkylN2S2 chelator; xe2x80x94O-alkylN2S2 chelator, -alkylN2S2Tc chelator; xe2x80x94O-alkylN2S2Tc chelator.
Preferred substituents for the above general formula are as follows: n is preferably 0; X is preferably xe2x80x94Oxe2x80x94R1, where R1 is preferably xe2x80x94CH3; Ar is preferably phenyl or napthyl (1- or 2-napththyl), substituted at any two positions with R3a, and R3b; e.g., R3a and R3b may independently be xe2x80x94Cl, xe2x80x94H. Particularly preferred compounds are O-1617; O-1630; O-1833; O-1925, described below in Table 1.
The second general class of compounds (which we generally term tetrahydropyranyl esters or THP esters) generally have one of the following three formulas: 
WHERE:
n is 0, 1, 2, or 3;
 greater than X is  greater than CH2;  greater than CHY;  greater than C(Y,Z);  greater than Cxe2x95x90O;  greater than O;  greater than S;  greater than SO;  greater than SO2;  greater than NSO2;  greater than NSO2R3; or  greater than Cxe2x95x90CYZ;
where Y and Z are independently selected from H; Br; Cl; I; F; OH; OCH3; CF3; NO2; NH2; CN; NHCOCH3; N(CH3)2; (CH2)mCH3, where m=0-6; COCH3; alkyl, alkenyl, alkynyl, allyl, isopropyl, isobutyl;
xe2x80x94Ar=either
a) phenyl substituted at any two positions with R1a and R1b, where R1a and R1b are as defined in options xe2x80x9cI.xe2x80x9d or xe2x80x9cII.xe2x80x9d, below; or
b) 1-napththyl or 2-naphthyl, substituted at any two positions with R1a and R1b where R1a and R1b are as defined in option xe2x80x9cI.xe2x80x9d, below);
OPTION I for R1a, and R1b (phenyl or naphthyl substitutions)
xe2x80x94R1a and xe2x80x94R1b are independently selected from: xe2x80x94H; xe2x80x94Br; xe2x80x94Cl; xe2x80x94I; xe2x80x94F; xe2x80x94OH;xe2x80x94OCH3; xe2x80x94CF3; xe2x80x94NO2; xe2x80x94NH2; xe2x80x94CN; xe2x80x94NHCOCH3, xe2x80x94C(CH3)3, xe2x80x94(CH2)qCH3 where q=0-6; xe2x80x94COCH3; xe2x80x94F (at the 2, 3 or 4 position), xe2x80x94Cl (at the 2, 3 or 4 position); xe2x80x94I (at the 2, 3 or 4 position); alkyl; alkenyl; alkynyl; allyl; iospropyl; isobutyl; -alkylN2S2 chelator, -alkylN2S2Tc chelator; or COR4, where R4 is defined below;
xe2x80x83OR
OPTION II. for R1a, and R1b (phenyl substitutions)
xe2x80x94R1a and xe2x80x94R1b as a pair are independently selected from the following pairs: 3,4-diCl; 3,4, diOH; 3,4-diOAc; 3,4-diOCH3; 3-OH, 4-Cl; 3-OH, 4-F; 3-Cl, 4-OH; or 3-F, 4-OH;
xe2x80x94R2=xe2x80x94COOCH3; xe2x80x94COR 4; -alkyl; -alkenyl; -allyl; -iodoallyl; alkynyl; -isoxazole; -oxadiazole; -oxazole; -alkylN2S2 chelator; xe2x80x94O-alkylN2S2 chelator. -alkylN2S2Tc chelator; xe2x80x94O-alkylN2S2Tc chelator; where,
xe2x80x94R4 is=xe2x80x94NHR5; morpholinyl; piperidinyl; xe2x80x94CH3; xe2x80x94CH2CH3; CH2(CH2)rCH3 where r=0, 1, 2, or 3; alkyl; alkenyl; alkynyl; allyl; isopropyl; iodoallyl; O-iodoallyl; -isobutyl; xe2x80x94CH2SO2; -alkylN2S2 chelator, -alkylN2S2Tc chelator; O-alkylN2S2 chelator; or xe2x80x94O-alkylN2S2Tc chelator; and
xe2x80x94R5 is= -alkyl; -alkenyl; -allyl; -iodoallyl; -alkynyl; -isoxazole; -oxadiazole; -oxazole; -alkylN2S2 chelator; xe2x80x94O-alkylN2S2 chelator; -alkylN2S2Tc chelator; xe2x80x94O-alkylN2S2Tc chelator.
Preferred compounds are those with the following substituents: X is preferably O; n is preferably 1; preferably the compound has formula A, above; R2 is preferably xe2x80x94COR4, most preferably xe2x80x94COOCH3; xe2x80x94Ar is preferably phenyl substituted at any two positions with R3a, and R3b, e.g., where R3a, and R3b are independently selected from xe2x80x94H and Cl. R4 is xe2x80x94OCH3 or xe2x80x94C2H5. Particularly preferred compounds are compounds: 1a (compound O-1793), 1b (compound O-1792), 2a (compound O-1794), 2b (compound O-1783), and the corresponding carboxylic acids, 3a, 3b, 4a, or 4b.
Compounds of the above formula which demonstrate monoamine transport affinity are useful for labeling receptor-expressing cells using in vitro techniques that are generally known to those skilled in the field and are generally described below. They may also be used for in vivo imaging in the conditions described above and to treat various medical indications, including attention deficit hyperactivity disorder (ADHD), Parkinson""s disease, cocaine addiction, smoking cessation, weight reduction, obsessive-compulsive disorder, various forms of depression, traumatic brain injury, stroke, and narcolepsy.
The invention also includes methods of making medicaments for treating the above indications, as well as pharmaceutical compositions comprising the compounds formulated to treat those indications, e.g., with a pharmaceutically acceptable carrier.
The details of one or more embodiments of the invention are set forth in the accompanying structures and the description below. Other features, objects, and advantages of the invention will be apparent from the following description and structures, and from the claims.